Preclinical and clinical studies have shown that Photodynamic Therapy (PDT) augments the host immune response by unknown mechanisms. Previous studies, which have largely been descriptive, have shown that 1) the tumor response to PDT is augmented by an intact immune system; 2) PDT promotes the formation of immune memory cells; 3) PDT enhanced tumor immunity is mediated by T cells. We have made the novel discovery that the direct effects of Photofrin (Pf)-PDT on tumor cells is sufficient to stimulate the host anti-tumor response and that the ability to stimulate an antitumor response can be correlated to activation of antigen-presenting cells (APCs). We have also shown that alterations in tumor immunogenicity by PDT are dependent upon the inherent tumor immunogenicity and the PDT protocol employed. These data have led to the hypothesis that PDT treatment results in the expression of immune mediators that are able to activate APCs, which stimulate tumor specific T cells and trigger the initiation of a cell-mediated antitumor immune response. We further hypothesize that the ability to activate APCs is dependent upon the photosensitizer, the PDT protocol employed and the immunogenicity of the tumor. The overall goal of this proposal is to understand how PDT enhances tumor cell immunogenicity and the mechanisms that lead to the augmentation of the host immune response. In Specific Aim I we will examine the role of HSP and inflammatory cytokines in the ability of PDT to enhance tumor immunogenicity. In Specific Aim II we will examine the role of direct and secondary effects of PDT on the activation of the host immune response in vivo as a function of PDT protocol and will examine the ability of the enhanced immune response to combat distant disease. In Specific Aim III we will use transgenic mouse models and tetramer and ELISPOT analyses to determine the kinetics and characteristics of tumor specific T cells that have been activated in response to PDT. Finally, in Specific Aim IV we will expand upon our original findings that Photofrin-PDT-generated tumor cell lysates are effective anti-cancer vaccines by determining whether PDT vaccines are able to augment the host immune response against established tumors and thus promote tumor control. The studies outlined in this proposal are primarily mechanistic and will point the way toward the design of PDT protocols with optimal immune enhancing capabilities, which could lead to enhancement of long-term control of tumors within and outside the treatment field.